EMEA基因毒性杂质限度指南DOCWord下载.docx

1、欧洲共同体药物评审委员会（EMEA）COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE人用药品委员会（CHMP） GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIES基因毒性杂质限度指南 DESCUSSION IN THE SAFETY WORKING PARTY安全工作组之内的讨论June 2002-October 2002TRANSMISSION TO CPMPCPMP传递December 2002RELEASE FOR CONSULTATION专家讨论DEADLINE FOR COMMENTS建议收集最后期

2、限March 2003DISCUSSION IN THE SAFETY WORKING PARTY AND QUALITY WORKING PARTY安全工作组和质量工作组之间的讨论June 2003-February 2004转移给CPMPMarch 2004RE-RELEASE FOR CONSULTATION再次放行给顾问团June 2004收集意见的最后期限December 2004February 2005-May 2006ADOPTION BY CHMP被CHMP采用28 June 2006DATE FOR COMING INTO EFFECT生效日期01January 2007K

3、EYWORDS关键词Impurities; Genotoxicity; Threshold of toxicological concern （TTC）; Structure activity relationship （SAR）GUIDLINE ON THE LIMITS OF GENOTOXIC IMPURITIESTABLE OF CONTENTS 目录EXECUTIVE SUMMARY 内容摘要. 31. INTRODUCTION 介绍. 32. SCOPE 范围 . 33. LEGAL BASIS法 律依据. 34. TOXICOLOGICAL BACKGROUND 毒理学背景. 4

4、5. RECOMMENDATIONS 建议. 45.1 Genotoxic Compounds With Sufficient Evidence for a Threshold-Related Mechanism具有充分证据证明其阈值相关机理的基因毒性化合物. 45.2 Genotoxic Compounds Without Sufficient Evidence for a Threshold-Related Mechanism不具备充分证据支持其阈值相关机理的基因毒性化合物. 55.2.1 Pharmaceutical Assessment药学评价. 55.2.2 Toxicologica

5、l Assessment毒理学评价. 55.2.3 Application of a Threshold of Toxicological Concern 毒理学担忧阈值应用. 55.3 Decision Tree for Assessment of Acceptability of Genotoxic Impurities基因毒性杂质可接受性评价决策树. 7REFERENCES. 参考文献. 8EXECUTIVE SUMMARY 内容摘要The toxicological assessment of genotoxic impurities and the determination of

6、acceptable limits for such impurities in active substances is a difficult issue and not addressed in sufficient detail in the existing ICH Q3X guidances. The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment

7、 of acceptable limits. In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach

8、 as defined by the Threshold of Toxicological Concern （TTC） is proposed. A TTC value of 1.5 g/day intake of a genotoxic impurity is considered to be associated with an acceptable risk （excess cancer risk of 1 in 100,000 over a lifetime） for most pharmaceuticals. From this threshold value, a permitte

9、d level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.基因毒性杂质的毒理学评估和这些杂质在活性药物中的可接受标准的测定是一件困难的事情，并且在现有的ICH Q3X指南中也没有详细的规定。现有的关于基因毒性杂质的相关数据是容易变化的，也是对杂质可接受标准如何进行评价的主要影响因素。如果缺少风险评估方法所

10、需要的数据，比如，致癌作用的长期研究数据，或为基因毒性的阀值提供证据的数据，一般建议使用一般通用的被定义为毒理学关注的阈值（TTC）的方法。一个“1.5g/day”的TTC值，即相当于每天摄入1.5g的基因毒性杂质，被认为对于大多数药品来说是可以接受的风险（一生中致癌的风险小于十万分之1）。按照这个阀值，可以根据这个预期的每日摄入量计算出活性药物中可接受的杂质水平。较高的临界值可以在特定的条件下，如短期暴露周期等，进行推算。1. INTRODUCTION 介绍A general concept of qualification of impurities is described in the

11、 guidelines for active substances （Q3A, Impurities in New Active Substances） or medicinal products （Q3B, Impurities in New Medicinal Products）, whereby qualification is defined as the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level（s） specified. In the case of impurities with a genotoxic potent